Malaria continues to be one of the most virulent infectious diseases and accounts for the death of almost 1 million people a year. Unlike most viral infections, children usually have repeated clinical episodes, but by adulthood, most individuals living in endemic areas are protected against disease. Immunoglobulin (Ig) molecules isolated from a protected adult can be used to passively transfer protection to naive individuals indicating a key role for antibody-mediated immunity. Cellular immunity mediated by CD8 T-cells and IFN? has also been implicated in protection against the initial liver stages of the infection in experimental models, but the significance of this type of immunity during natural human infections has been difficult to evaluate. Rigorous analysis of protective immune responses in the field is hindered by an inability to control and define parasite exposure. Animal studies, while allowing strain and inoculation controls, are difficult to apply to human infections due to differences across host and parasite species. The goal of the present study is to systematically evaluate the immune response to an initial Plasmodium falciparum (Pf) infection and 4 subsequent Pf infections in 7 healthy volunteers, each serving as their own control. The use of the human malaria challenge model allows the timing of parasite exposure to be controlled and therefore the early response to infection can be directly monitored. The 7 volunteers will first be challenged with uninfected mosquitoes to establish a baseline and then 5 sequential exposures to Pf-infected mosquitoes. Clinical symptoms will be monitored daily and the volunteers will be treated with standard dose of Coartem at the first positive malaria smear or on day 20 if no parasites are observed by then. Blood samples will be collected for transcription profiling, PBMC immunophenotyping and plasma characterization prior to and every 2 days after the challenge until treatment or day 20, if no parasites are observed. Additionally, plasma cells will be collected on day 20 ? 1 for Ig repertoire evaluation. This systematic study of the clinical and immune response to repeated Pf infections will provide insights into the development of protection from severe disease that can be used to design more effective control strategies.